3-(2′-Bromopropionylamino)-benzamides as novel S-phase arrest agents

Article abstract of DOI:10.1016/j.bmcl.2007.10.016

We report the synthesis, antiproliferative activity, and SAR of novel 3-(2′-bromopropionylamino)-benzamides. Many of the benzamide compounds showed potent cytotoxicities against Molt-3 leukemia cells. Several compounds exihibited cytotoxicities (under 6.5

Full text of DOI:10.1016/j.bmcl.2007.10.016

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6847–6852
3-(20-Bromopropionylamino)-benzamides as novel
S-phase arrest agents
Laixing Hu,a,b Zhuo-rong Li,b Jian-Nong Li,b Jinrong Qu,c
Jian-Dong Jiangb,* and David W. Boykina,*
aDepartment of Chemistry, Georgia State University, Atlanta, GA 30303-3083, USA
bInstitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College,
Beijing 100050, People’s Republic of China
cDepartment of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
Received 4 September 2007; revised 4 October 2007; accepted 5 October 2007
Available online 17 October 2007
Abstract—We report the synthesis, antiproliferative activity, and SAR of novel 3-(20-bromopropionylamino)-benzamides. Many of
the benzamide compounds showed potent cytotoxicities against Molt-3 leukemia cells. Several compounds exihibited cytotoxicities
(under 6.5 lM) against five solid tumor cell lines. The mechanism of action of the most potent benzamide 10l does not involve tar-
geting on tubulin but it causes cell cycle S-phase arrest. This active S-phase arrest agent merits further investigation.
Ó 2007 Elsevier Ltd. All rights reserved.
Cell cycle control is crucial for error-free transmission of
the entire genetic material to subsequent generations.
Defective regulatory function results in genetic modifi-
cations that contribute to tumorigenesis. The loss of cell
cycle control leading to deregulated cell proliferation is a
hallmark of cancer. Many chemotherapeutic agents in
clinical use kill rapidly dividing cancer cells by inducing
cell cycle arrest at various phases and subsequently lead
to apoptosis. For example, antitubulin agents, taxanes,
and vinca alkaloids target tubulin dynamics which in-
duce G2/M phase arrest; on the other hand, DNA topo-
isomerase I inhibitors, camptothecin analogues, cause
the S-phase arrest of cancer cells.1,2 However, multi-
drug resistance (MDR) and undesired side effects have
limited their clinical use.3 Thus, it is very important to
develop effective anticancer agents with both improved
safety profiles and novel mechanism of actions.
panel of thirteen human tumor cell lines including
MDR B-cell lymphoma.4 JIMB01 interferes with the
assembly of microtubules, arrests the cell cycle at G2/
M phase, and induces apoptotic cell death in a variety
of cancer types. Moreover, JIMB01 has shown promis-
ing in vivo efficacy in a hepatocarcinoma (Bel-7402) tu-
mor model.4 With the goal to elucidate the SAR and
further enhance the anticancer activity of JIMB01, we
synthesized a series of novel 3-(20-bromopropionylami-
no)-benzamides, which display more potent antiprolifer-
ative activity and a different mechanism of action is
shown for 10l.
The SAR studies of 3-haloacetamido benzoylurea com-
pounds (Chart 1, 2–5) have shown that the 3-haloace-
tamido group and the acylurea unit must be in a meta-
relationship for potent cytotoxicity and antitubulin
activity.5 In the original work, replacement of the acylu-
rea group with an ethyl ester group resulted in 3-halo-
acetamido benzoyl ethyl ester compounds (Chart 1, 6–
9).6,7 The 3-iodo or bromoacetamido benzoyl ethyl es-
ters displayed improved solubility and maintained the
inhibitory effect on microtubule assembly. However, this
modification induced different effects on the tumor cell
cycle: 3-iodoacetamido benzoyl ethyl ester blocked at
the G1–S transition in addition to its activity in G2/M
phase. A related simple benzamide, 3-aminobenzamide,
a poly (ADP-ribose) polymerase (PARP) inhibitor, was
We have recently reported a small molecule compound 3-
(20-bromopropionylamino)-benzoylurea(JIMB01) (Chart
1, 1) which has strong antiproliferative activities in a
Keywords: Benzamides; Antiproliferative; S-phase arrest.
*
Corresponding authors. Tel.: +86 10 6316 5290; fax: +86 10 6301
7302 (J.-D.J.); tel.: +1 404 413 5498; fax: +1 404 413 5505
(D.W.B.); e-mail addresses: jiandong.jiang@mssm.edu; dboykin@
gsu.edu
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.016

6848
L. Hu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6847–6852
Scheme 2. Reagents and condition: (a) NEt3, DMF; (b) SnCl2, EtOH,
reflux; (c) 2-bromopropionyl bromide, DMF.
Scheme 3. Reagents and condition: (a) NEt3, DMF; (b) SnCl2, EtOH,
reflux; (c) 2-bromopropionyl bromide, DMF.
Chart 1. Small molecule antiproliferative agents: benzoylurea, ethyl
ester and benzamides.
shown to affect DNA synthesis and to inhibit DNA re-
pair.8,9 Additionally, several other classes of benzamides
or pyridinyl amides have been reported such as tubulin,
protein tyrosine kinase, or NF-jB inhibitors.10–13 Thus,
we explored the replacement of the acylurea group with
the amide group in the lead compound JIMB01. Here,
we report the synthesis, cytotoxicity, SAR analysis,
and preliminary mode of action information for this ser-
ies of novel benzamide compounds.
Scheme 4. Reagents and condition: (a) NEt3, DMF; (b) SnCl2, EtOH,
reflux; (c) 2-bromopropionyl bromide, DMF.
cedure, as shown in Scheme 5. Condensation of 3-nitro-
benzoylisocyanate 25 with aniline 16 following reported
procedures gave the benzoylurea compound and ulti-
mately the final compound 26 (see Scheme 6).15
The synthesis of 3-(20-bromopropionylamino) benzam-
ides is shown in Schemes 1–4. The benzoyl chlorides
(either commercially available or directly prepared from
the corresponding benzoic acid) were allowed to react
with alkyl or arylamines in the presence of triethylamine
in DMF to yield the nitrobenzamides. Then reduction of
the nitro group by SnCl2Æ2H2O in ethanol at reflux
yielded the corresponding amino compounds.14 Finally,
acylation with 2-bromopropionyl bromide afforded the
desired benzamides.5 The corresponding sulfonamide
compound 24 was prepared from 3-nitrobenzenesulfo-
nyl chloride 23 by reaction with 3,4,5-trimethoxyaniline
16, followed by our general reduction and acylation pro-
The novel series of 3-(20-bromopropionylamino) benz-
amides and their analogues were evaluated for their
antiproliferative activity against the Molt-3 leukemia
cell line and were compared with the lead compound
JIMB01, as shown in Table 1.16 Fourteen of the 28
Scheme 5. Reagents and condition: (a) NEt3, DMF; (b) SnCl2, EtOH,
reflux; (c) 2-bromopropionyl bromide, DMF.
Scheme 1. Reagents and conditions: (a) SO2Cl, EtOAc, reflux; (b) R3-
NH2, NEt3, DMF; (c) SnCl2, EtOH, reflux; (d) 2-bromopropionyl
bromide, DMF; (e) HCl (gas), EtOAc.
Scheme 6. Reagents and condition: (a) 1,4-dioxane; (b) SnCl2, EtOH,
reflux; (c) 2-bromopropionyl bromide, DMF.

L. Hu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6847–6852
Table 1. Antiproliferative activity of new compounds in Molt-3 T-cell leukemia cells
6849
Compound
R1
R2
X
R3
IC50 (lM)a
JIMB01
10a
H
H
H
H
H
H
OMe
F
H
H
H
H
H
H
H
H
H
OH
F
–CONHCONH2
–CONH–
–CONH–
–CONH–
–CO–
—
1.60
8.94
>10
>10
>10
0.67
4.24
2.20
2.25
1.08
0.42
0.80
0.12
0.51
0.62
0.61
2.00
0.25
>10
0.47
0.85
0.50
1.66
1.51
5.66
1.27
4.22
5.72
1.79
0.014
0.09
–CH2CH2CH3
–CH2CH2CH2CH3
–CH2CH2NMe2ÆHCl
1-MePiperizine-4-ylÆHCl
3,4,5-OMe3Ph
3,4,5-OMe3Ph
3,4,5-OMe3Ph
3,4,5-OMe3Ph
3,4,5-OMe3Ph
3,4,5-OMe3Ph
4-MeOPh
10b
10c
10d
10e
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–CONH–
–NHCO–
–SO2NH–
–CONHCONH–
10f
10g
10h
10i
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
10j
10k
H
H
H
H
H
H
F
10l
10m
3,4-OMe2Ph
4-OH-3-OMePh
3,4-O–CH2–O–Ph
3,5-OMe2Ph
10n
10o
10p
10q
4-FPh
4-OMePh
10r
10s
F
4-OEtPh
3,4-OMe2Ph
F
10t
10u
F
4-OH-3-OMePh
2-OMePy-4-yl
6-OMebenzothiazole-2-yl
Carbazole-3-yl
3,4,5-OMe3Ph
3,4,5-OMe3Ph
3,4,5-OMe3Ph
F
10v
10w
H
H
H
H
H
22
24
26
17
19
Podophyllotoxin
CA-4
a Values were determined in duplicate as described in Ref. 16.
compounds prepared were more active than lead com-
pound JIMB01. Eleven compounds showed IC50 values
under 1 lM.
methoxyphenyl group is found in many antitubulin
compounds, such as colchicine, podophyllotoxin, and
combretastatin A-4 (CA-4),17 we first evaluated the
influence of 3,4,5-trimethoxyphenyl group on this series
of 3-(20-bromopropionylamino) benzamide compounds.
The 3,4,5-trimethoxyphenyl compound 10e (IC50 value
0.67 lM) is 2.3 times more potent than JIMB01.
We first evaluated the cytotoxic effect of N-alkyl substi-
tution of benzamide. The synthesized compounds 10a
and 10b showed decreased potency by more than five-
fold compared to lead compound JIMB01. In order to
improve water solubility, we also introduced dimethyl-
aminoethyl and N-methylpiperizine groups and evalu-
ated the cytotoxicies of their hydrochloride salt. While
the compounds 10c and 10d were more water-soluble,
unfortunately, they showed lower activity. These results
demonstrated that N-alkyl group and cation containing
side chains were not suitable for potent antiproliferative
activity.
The effect of various substitutions on the benzene ring in
the benzamides was also examined. Substitution of R1 of
10 with methoxy, fluoro, or chloro (10f–10h) reduced
cytotoxicity by 3–7 times. However, when R2 was substi-
tuted with hydroxy (10i), inhibitory activity comparable
to compound 10e was observed. Substitution of R2 with
a fluorine atom (10j) led to a modest increase in antipro-
liferative activity.
Replacement of the N-alkyl group with N-aryl group
yielded novel N-aryl benzamides. Because the 3,4,5-tri-
We further evaluated the influence of various substitu-
tions on the N-phenyl ring of the benzamide. A single

6850
L. Hu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6847–6852
methoxy substitution of the phenyl ring (10k) led to a
slight loss of potency. However, 3,4-dimethoxy substitu-
tion of the phenyl ring (10l) led to a 5.5-fold increase in
activity relative to 10e. 4-Hydroxy-3-methoxy, 3,4-O–
CH2–O, and 3,5-dimethoxy phenyl substituted benzam-
ides (10m–10o) showed similar cytotoxicities to that of
the 3,4,5-trimethoxyphenyl compound 10e, all showed
greater activity than the lead compound JIMB01. These
results suggest that mono, di, or trimethoxy substitu-
tions on the 3, 4, or 5 position of phenyl ring are all well
tolerated and increase the activity. The 3,4-dimethoxy
substitution seems to be the most effective. However,
changing 4-methoxy to a 4-fluoro (10p) yielded a three-
fold loss of activity.
Although these compounds’ activities against solid tu-
mor cell lines are less potent than against Molt-3 leuke-
mia cell line (IC50 < 0.67 lM), the IC50 values of these
most potent N-aryl benzamides were between 0.86 and
6.48 lM. The 3,4-dimethoxy substituted benzamide
compound 10l is slightly more active than the 3,4,5-tri-
methoxyphenyl substituted compound 10e against these
human solid tumor cell lines. However, the 4-hydroxy-3-
methoxy compound 10m showed different sensitivities
compared to the 3,4-dimethoxy and 3,4,5-trimethoxy
substitutions inhibiting these solid tumor cells. The com-
pound 10j with ortho-fluorine substitution showed simi-
lar activities with non-fluorine compound 10e. The 4-
methoxyphenyl and 2-methoxy pyridine-4-yl com-
pounds 10q, 10u with ortho-fluorine substitution also
displayed comparable activities with 3,4,5-trimethoxy
substituted compound 10e. These results suggest that
the substitutions with various methoxy groups and
ortho-fluorine are of little influence on the cytotoxicities
against these five solid tumor cell lines, which is different
from that of the Molt-3 leukemia cell line.
Although introduction of a fluorine ortho to the acetam-
ide (R1) did not improve potency, we synthesized com-
pounds 10q–10u with an ortho-fluorine to the
benzamide (R2). The results were different compared
to the corresponding non-ortho-fluorine compounds.
ortho-Fluorine substitution improved activity for 3,4,5-
trimethoxyphenyl and 4-methoxyphenyl compounds
and reduced it for 3,4-dimethoxy and 4-hydroxy-3-
methoxy substituted compounds. It is also surprising
to note that replacement of 4-methoxyphenyl by 4-eth-
oxyphenyl led to a dramatic loss of activity. The 2-
methoxypyridine-4-yl substituted ortho-fluorine com-
pound 10u displayed similar activity to that of the 3,4-
dimethoxyphenyl compound 10s. The 4-methoxyphenyl
compound 10q exihibited the most potent activity in this
series of ortho-fluorine substituted benzamides.
The lead compound JIMB01 has shown complete inhibi-
tion of free tubulin assembly at a concentration of
4 lM.4 The mechanism of action of JIMB01 involves
targeting on tubulin which blocks the cell cycle at the
G2/M phase. To investigate whether the antiproliferative
activities of the novel N-aryl benzamide compounds in-
volved interaction with tubulin, the most active com-
pound 10l was evaluated for inhibition of
polymerization of purified tubulin in a cell-free system.
The results are shown in Figure 1. Vincristine was used
as a positive control. Inhibition of tubulin assembly was
examined by compound 10l at concentrations of 0.5–
10 lM. Surprisingly, the results showed that the com-
pound 10l does not significantly interfere with the
assembly of microtubules. Then, we further examined
the influence of 10l on the cancer cell cycle using flow
cytometric analysis with T-cell leukemia cells (Fig. 2).
Treatment with 10l at a concentration of 6.14 lM for
6 h induced a major shift from G0/G1 to the S-phase
(52.9%) compared to control (32.2%). The S-phase peak
increased continuously from 6 to 12 h (62.7%) and
maintained a high level at 24 h (61.9%). However, the
G2/M phase proportion of cells was little changed under
treatment with 10l. These results further confirmed that
the mechanism of action of the benzamide compound
10l was different from the lead compound JIMB01 and
that it is a novel S-phase arrest agent. As mentioned pre-
viously, replacement of the acylurea group with an ethyl
ester group resulted in 3-iodoacetamido benzoyl ethyl
Replacement of the N-phenyl ring with 2-(6-methoxy)-
benzothiazolyl (10v) and 3-carbazolyl groups (10w) gave
2- to 2.5-fold loss in activities as compared to compound
10e; however, these two compounds are still as potent as
the lead compound JIMB01. In order to understand the
importance of the amide linkage, we further synthesized
the benzamide 22, the phenylsulfonamide 24, and the
benzoylurea 26. All of these compounds displayed re-
duced cytotoxicities. Moving the amide group from
meta to para or ortho position (17, 20) also resulted in
loss of inhibitory activity. These results revealed that
the amide linkage and the position on the phenyl ring
are important for antiproliferative activity.
We further evaluated the antiproliferative activities of
several potent compounds 10e, 10j, 10l, 10m, 10q, 10u
against a panel of five human solid tumor cell lines
in vitro. Table 2 contains these results along with com-
parative data for CA-4 and podophyllotoxin.16
Table 2. Antiproliferative activities of 10e, 10j, 10l, 10m, 10q, 10u, CA-4, and podophyllotoxin in human cancer cell lines
Cell line
Human tumor
IC50 (lM)a
10e
10j
10l
10m
10q
10u
CA-4
Podophyllotoxin
Molt-3
MCF-7
Bel-7402
DU-145
PC-3
T-cell leukemia
Breast cancer
Hepatoma
0.67
1.47
2.64
1.93
2.46
2.26
0.42
2.11
2.05
2.03
2.18
4.16
0.12
1.23
2.33
1.87
2.36
1.40
0.51
0.86
5.26
6.48
3.13
1.22
0.25
1.39
3.37
6.45
2.43
2.56
0.50
2.20
2.70
2.35
2.42
2.57
0.009
0.012
0.010
0.009
0.003
0.003
0.014
0.015
0.009
0.052
0.010
0.012
Prostate cancer
Prostate cancer
Melanoma
DND-1
a Values were determined in triplicate as described in Ref. 16.

L. Hu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6847–6852
6851
0.35
0.3
compound JIMB01. Many new benzamide compounds
showed more potent antiproliferative activities against
Molt-3 leukemia cells than the lead compound JIMB01.
Several compounds showed effective activities against
five solid tumor cell lines. Preliminary mechanism of ac-
tion studies demonstrated that the most potent benzam-
ide compound 10l does not inhibit tubulin
polymerization and arrests the cancer cell cycle at S-
phase, which is different from the lead compound
JIMB01. This series of benzamide compounds merits
further studies as novel S-phase arrest agents.
Vin
PTX
DMSO
10uM
4uM
2uM
1uM
0.5uM
0.25
0.2
0.15
0.1
0.05
0
0
5
10
15
20
25
30
35
Time (min)
Acknowledgments
Figure 1. Effect of 10l on tubulin assembly.16 Free purified b-tubulin
from bovine brain (1 mg/mL) in reaction buffer was incubated with
GTP and Mg2+ at 37 °C for assembly in the absence or presence of 10l
(0.5–10 lM), vincristine (20 lM) or paclitaxel (20 lM). Tubulin
assembly was determined every 2 min by OD at 340 nm. Each point
represents the mean of two independent experiments.
We thank the National Natural Science Foundation of
the PR China (30500630) and the Technology Develop-
ment Program of the Georgia State University Center of
Biotechnology and Drug Design for support of this
work.
6 h
Control
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0
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acylurea with an amide group in the lead antitubulin

6852
L. Hu et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6847–6852
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